Are You Confident of the Diagnosis?

Polycystic ovarian syndrome (PCOS) presents with a variable constellation of symptoms. Establishing precise diagnostic criteria has been challenging. In 2003, the Rotterdam Consensus Group defined PCOS by the presence of two out of three of the following factors: oligo- or anovulation, signs of hyperandrogenemia, and polycystic ovaries on ultrasound imaging.

What you should be alert for in the history

The patient’s history is the most important factor in diagnosing PCOS. Menarche occurs at the average age of 12 to 13 years. The most common manifestation of PCOS is irregularity in the menstrual cycle, which begins shortly thereafter, with oligomenorrhea (75%-90%) occurring more frequently than amenorrhea (30%). Teenage patients are often prescribed oral contraceptive pills (OCPs) to regulate their menstrual cycle without establishing a diagnosis for what is widely considered developmentally normal. OCPs, in turn, decrease serum androgen levels and may mask PCOS symptoms for years. Many patients present later after having discontinued the OCP with concerns of oligomenorrhea and/or infertility.

Women with PCOS also present with complaints related to clinical hyperandrogenism. The second most common symptom in PCOS is hirsutism. Other related complaints include acne, generalized diffuse hair loss, rapid weight gain, and extreme difficulty in losing weight. Keeping in mind the varied clinical picture, up to 40% of PCOS patients report no symptoms of androgen excess at presentation.

Family history may provide clues to diagnosis as well. As is has been postulated that PCOS carries an autosomal dominant inheritance pattern, there may be a history of irregular periods, acne, excess hair growth, and infertility or difficulty conceiving children. Male carriers of PCOS may display premature balding. Addtionally, extended family members may carry the diagnosis of type 2 diabetes mellitus.

Characteristic findings on physical examination

A thorough physical examination is a mandatory component in the diagnosis of PCOS. It is, however, important to remember that there are significant phenotypic variations of the disease and not all women with PCOS display the typically associated symptoms.

Many PCOS patients have elevated blood pressure with systolic pressures up to to 135 mmHg and diastolic pressures up to the low 90 mmHg range. It has been reported that 30-75% of PCOS patients are overweight or obese. Central obesity is a characteristic feature with fat deposition noted around the abdomen, upper arms, and upper back. There may be mild cliteromegaly and underdeveloped labia.

Cutaneous findings on physical examination can be divided into two categories - signs of hyperandrogenemia and signs of hyperinsulinemia. Hirsutism is considered the leading indicator of excess circulating androgens. Terminal hairs may be found on the face, chest, between the breasts, in the periareolar area, and lower abdomen. The finding of only few terminal hairs in this distribution should alert the clinician to increased androgen production.

Acne is another sign of hyperandrogenemia but is less prevalent in PCOS than hirsutism (Figure 1). It can be of variable severity but may be severe, persistent, recalitrant to conventional treatments, and may be present in a more androgen-sensitive distribution such as the chest, back, and buttocks.

Figure 1.

Acne and hirsutism in PCOS.

Diffuse hair loss is common in the face of elevated circulating androgens (Figure 2). Dispropotionately small, underdeveloped breasts and seborrhea may be clues to diagnosis as well. Cutaneous manifestations of hyperinsulinemia include acanthosis nigricans and acrochordons.

Figure 2.

Androgenic alopecia in PCOS.

Expected results of diagnostic studies

Laboratory testing requires obtaining tests to both support the diagnosis of PCOS and rule out other entities. The clinician should note that OCPs affect the levels of bioavailable testosterone, luteinizing hormone (LH) and follicle stimulating hormone (FSH) thereby rendering the results of hormone testing while a patient is on OCPs useless. Discontinuation of OCPs for at least 6 weeks before testing is recommended.

- LH and FSH. The ratio is usually greater than 2.5 to 1. LH elevation is pathognomoic of PCOS but may also be elevated just before menstruation. If there is a question, confirm that phlebotomy did not take place 14 days after a menstrual period.

- Total testosterone. Level greater than 50 ng/dL is considered elevated. It is the most sensitive marker for hyperandrogenemia and is aberrantly high in one-third of women with PCOS. The standard cutoff for “normal” Is 70 ng/dL but it has been found that most women with levels higher than 50 ng/dL display symptoms of hyperandrogenism.

- Free testosterone. This will be elevated frequently as well.

- Dehydroepiandrosterone sulfate (DHEA-S). 200-300 ng/dL is considered elevated despite normal cutoffs designated; DHEA-S may be the sole elevated androgen in PCOS. Levels may vary among between races and age groups.

- Thyroid-stimulating hormone. Normal in PCOS

- Prolactin. Normal in PCOS.

- 17-alpha-hydroxyprogesterone. Normal in PCOS.

Transvaginal sonography (TVS) classically shows cysts that are peripheral, multiple, and less than 10mm in diameter (aka “string of pearls”). A negative TVS in the face of a typical history and signs of hyperandrogenism does not exclude PCOS.

Diagnosis confirmation

The differential diagnosis of PCOS includes the following conditions.

- Non-classical congenital adrenal hyperplasia (NCCAH). Patients exhibit signs of hyperandrogenism but menstrual irregularity is less common. These patients have a history of precocious puberty at 9 to 10 years of age. NCCAH is more common in women of Ashkenazi Jew, Greek, Italian, Latin, and Slavic descent. A morning 17-alpha- hydroxyprogesterone will be elevated. Note that PCOS and NCCAH may coexist with one another.

- Primary hypothyroidism. Patients present with oligomenorrhea and mild elevated androgens. A goiter may be detected as well as abnormal thyroid studies. Note that hypothyroidism is seen more commonly in PCOS than in women without PCOS.

- Prolactinoma/pituitary adenoma. Most patients experience galactorrhea and serum prolactin will be elevated.

- Cushing’s disease. Clinically there is elevated blood pressure, abdominal striae, and a history of easy bruising. 24-hr urine cortisol levels are often greater than 100.

Who is at Risk for Developing this Disease?

PCOS is the most common hormonal disorder affecting women of reproductive age. Its prevalence ranges from 6% to 10% in the United States. It is thought to be autosominal dominantly inherited.

What is the Cause of the Disease?

Pathophysiology

The pathogenesis of PCOS has yet to be clarified and is likely multifactorial in nature. There are two postulated theories, both which culminate in hyperandrogenemia. The first and most widely accepted is that which poses insulin resistance as the hallmark of the disease process. Hyperinsulinemia, in turn, stimulates androgen production by the ovarian theca cells and also inhibits the production of SHBG by the liver.

The second hypothesis involves a derangement in the hypothalamic-pituitary axis. Hypothalamic dysfunction results in increased amplitude and pulse frequency of gonadotropin-releasing hormone (GnRH) which favors the production of LH over FSH. The resulting imbalance and relative LH excess favors the formation of ovarian androgens.

Systemic Implications and Complications

PCOS is a metabolic disorder with multiple systemic implications. It is a leading cause of infertility in women of reproductive age and patients with PCOS are at increased risk of developing hypertension, diabetes, and hyperlipidemia. A 2-hour oral glucose tolerance test is often used to evaluate for insulin resistance. Some practitioners prefer to order insulin levels or measure a fasting glucose to insulin ratio. A fasting lipid profile should also be ordered.

Patients should always be referred to a practitioner who is knowledgeable with respect to PCOS - either internal medicine, endocrinology, or obstetrics-gynecology. Ultimately, a multidisciplinary approach to management is the most beneficial strategy for these patients.

Treatment Options

Treatment options are summarized in Table I.

Table I.

Treatment options for polycystic ovarian syndrome

MEDICAL TREATMENT

SURGICAL PROCEDURES

PHYSICAL MODALITIES

Systemic Medications

Mechanical Hair Removal

Oral contraceptives

Spironolactone

Cyperoterone acetate

Finasteride

Metformin

Thiazolidinediones

Flutamide

Ketoconazole

Leuprolide

Cimetidine

Saw palmetto (Serenoa repens extract)

Topical Medications

Minoxidil

Eflornithine

Optimal Therapeutic Approach for this Disease

The most important treatment strategy is to address the patient’s diet, activity level, and weight. Improving nutrition, increasing physical activity, and weight loss are of paramount importance. This cannot be stressed enough to the patient. Androgen levels and ovarian function can improve with even a 5% decrease in body weight.

OCPs have been considered the first-line therapy in restoring regular menstrual periods and treating acne and hirsutism in PCOS. Supraphysiologic doses of estrogen enhance hepatic production of sex hormone binding globulin (SHBG), which then binds bioavailable testosterone. Choose wisely, as there are a wide variety of progestins used in OCPs. Some are more antiandrogenic in effect (norgestimate, desogestrol, and gestodene) while other are more androgenic (norgestrol and levonorgestrol).

The progestins drospirenone (derived from 15-alpha-spironolactone) and cyproterone acetate have been combined with ethinyl estradiol in the OCPs Yasmin® and Dianette®/Diane-35®, respectively. They are unique in that they both have antiandrogenic activity and have been effective in the treatment of acne. Dianette®/Diane-35® has been found to significantly reduce hirsutism in some studiies while the results with Yasmin® are varied. Dianette®/Diane-35®, however, is not available in the United States.

Recently, OCP use in PCOS has generated controversy. Studies in both obese and nonobese patients show an increase in insulin resistance after 3-6 months of therapy. Stressing the importance of lifestyle changes regarding weight loss and exercise in conjunction with OCP use as first-line treatment is recommended. Be more cautious when prescribing OCPs to women who are obese, insulin resistant, and who have a personal or family history of diabetes. Note that OCPs are contraindicated in women with a history of clotting disorders, cerebrovascular disease, hepatic dysfunction, smokers over 35 years of age, and those with an increased risk of breast cancer.

Spironolactone is an aldosterone antagonist that also has antiandrogenic properties. It inhibits ovarian and adrenal production of androgens, increases SHBG, decreases 5alpha-reductase activity, and blocks dihydrotestosterone (DHT) at the receptor level. While not consistent, spironolactone has been useful in the treatment of hirsutism at higher doses up to 200 mg daily. Some reports indicate that heavier patients require higher doses to see positive effects.

It has also been shown to be more effective (100mg daily) than both finasteride (5 mg daily) and cyproterone acetate (12.5 mg daily) but not as effective as flutamide (500mg daily). It may require up to 6 months of treatment to see maximum benefits and then can be maintained at the lowest dose that sustains the response.

With regard to alopecia, doses of 200mg daily have proven in upwards of 80% of cases to slow or stop progression of hair loss or result in hair growth. It has been found to be equally in efficacy to cyproterone acetate but inferior to flutamide.

It appears that spironolactone also results in decreased sebum production and is effective in the treatment of acne in PCOS. Lower doses (50-100 mg/d) appear to be effective when compared with the treatment of hirsutism and alopecia.

As spironolactone is a potassium-sparing diuretic, there is a theoretical risk of hyperkalemia. The risk of hyperkalemia in an otherwise healthy young woman is exceedingly low and many experienced clinicians have found monitoring potassium levels to be unnecessary in these patients. Monitoring serum potassium levels early in therapy for patients with other co-morbidites and advising against excessive intake of potassium-rich foods is reasonable, however.

Other common side effects include menstrual irregularities, GI upset, fatigue, headaches, breast tenderness, and polyuria. Most resolve spontaneously after 2 months. It is also is pregnancy category X and causes testicular feminization of a male fetus. For this reason and also because of the increased clinical benefit, spironolactone is most often used with an OCP.

Cyproterone acetate is an antiandrogen with weak progestational and glucocorticoid activity. It blocks androgens at the receptor level and also decreases testosterone levels by suppressing LH. Cyproterone acetate can be used by itself or in combination with ethinyl estradiol as Dianette®/Diane-35®. It has significant efficacy against the alopecia, hirsutism, and acne seen in PCOS. It is also well-tolerated but not available in the United States.

Finasteride competitively inhibits 5-alpha-reductase (type 2 >> type 1) and is the only FDA-approved agent for the treatment of male-pattern androgenic alopecia. There have been few investigations into its use in women for alopecia, hirsutism, and acne. In the past, doses of 5mg were recommended but more recently, finasteride 2.5 mg daily has proven effective in treating both alopecia and hirsutism. With regards to hair loss, the 2.5-mg dose was combined with an OCP/drospirenone. Time to response has varied from 3-12 months. It appears that finasteride is similar in efficacy to both spironolactone and flutamide in the treatment of hirsutism with time to response reported from 6-12 months.

Finasteride has only limited activity to the type 1 isoenzyme of 5-alpha-reductase which predominates in the pilosebaceous unit and thereby has limited to no effect on acne lesions. Side effects include xerosis, decreased libido, headaches, and gastrointestinal (GI) upset. It is category X in pregnancy and results in feminization of a male fetus, thereby mandating contraceptive use during treatment.

Metformin is a biguanide that decreases insulin resistance and indirectly reduces production of androgens by the ovarian theca cells. It is used commonly in the treatment of PCOS and is added to or replaces the OCP based on the patient’s profile and response to treatment. Metformin has been shown to promote normal menstrual cycling and ovulation by month 3 of therapy. It has also been shown to decrease androgens, decrease blood pressure, improve fasting insulin, and lower low-density lipoproteins. Experts have also shown that metformin can decrease the risk of diabetes and perhaps the risk of cardiovascular events as well.

In relation to the dermatologic manifestation of PCOS, metformin should not be considered as a first-line agent in the treatment of these conditions. While there have been reports that metformin is effective in patient with acne and severe hirsutism, currently there is no significant body of evidence to support these claims.

Metformin often causes GI side effects, including bloating, diarrhea, and nausea. Note that the resultant increased fertility can lead to unexpected pregnancies. There are no guidelines for dosage but it should be started at a low dose of 500mg daily and then titrated up to 2000 mg daily. Baseline and annual liver and renal function tests are prudent. It is contraindicated in patients with renal or hepatic dysfunction, and those that are at high-risk for lactic acidosis. Patients should be counseled to hold the medication before administration of iodine contrast media, surgical procedures, or prior to a period of excess alcohol ingestion.

Thiazolidinediones, including pioglitazone and rosiglitazone, are insulin-sensitizing agents and have shown to be effective in decreasing both insulin and androgen levels. There have been reports of an improvement in hirsutism after 2 months of therapy with pioglitazone and anecdotal reports of an improvement in acne lesions. The use of this class of drugs has been somewhat controversial in light of its side-effect profile. which includes weight gain, hepatotoxicity, and congestive heart failure.

Many practitioners reserve the thiazolidinediones for the non-obese PCOS patient. Note that troglitazone was withdrawn from the market secondary to severe hepatotoxicity and that rosiglitazone is under monitoring in the US and not available in Europe due to reports of increased risk of cardiovascular events.

Flutamide is a pure antiandrogen that blocks androgen receptors without affecting either glucocorticoid, progesterone, or estrogen receptors. Its mechanisms of action include blocking androgen receptors, interfering with the uptake of testosterone and DHT, and increasing androgen metabolism. Flutamide has been shown to be more efficacious than other antiandrogen agents in the treatment of hair loss, severe acne and hirsutism, particularly at doses of 500mg daily. Lower doses between 62.5mg daily and 250mg daily have also proven effective in the treatment of mild to moderate acne and hirsutism.

Many experts agree that combining flutamide with an OCP would yield even more superior results. There is a rare but serious risk of severe, fatal hepatotoxicity that discourages many practitioners from using flutamide. There have been no reports at doses less than 500mg daily but mild, transient hepatotoxicity has been reported at even lower doses. Other side effects include lethargy, decreased libido, mood changes, and possible effects on a male fetus.

Ketoconazole is an antifungal that has some antiandrogenic properties. A few studies have demonstrated some level of efficacy against hirsutism and acne. One study in particular found ketoconazole 400mg daily to yield better results in hirsutism than OCP, cyproterone acetate (100mg daily with OCP/cyproterone acetate), and spironolactone (100-200mg daily).

Cimetidine is an H2 blocker with weak antiandrogen properties. It may be a useful adjunct in the treatment of hirsutism and acne in PCOS. The recommended dosage is 300mg three times daily.

Leuprolide is a gonadotropin-releasing hormone agonist that suppresses gonadotropin and androgen formation. It can be used effectively with an OCP in the treatment of hirsutism.

Saw palmetto (Serenoa repens extract) is an herbal remedy that inhibits 5-alpha-reductase. It is most commonly used as a “natural” remedy to alleviate symptoms of benign prostatic hypertrophy. There has been one double-blind placebo-controlled study that demonstrated its efficacy in the treatment of androgenic alopecia.

Mechanical hair removal includes temporary procedures (plucking, waxing, shaving) and permanent procedures (electrolysis, laser hair removal). While permanent procedures are likely preferred they are often more costly. If using temporary methods, shaving is the recommended modality as the potential adverse cutaneous effects are less.

Eflornithine inhibits ornithine decarboxylase, is effective topically for hirsutism and can be easily combined with other therapies. Applied twice daily it causes miniaturization of hairs. Reponse rates have been estimated around 30%. As the effects are reversible, hair growth reportedly returns to pretreatment rates within 8 weeks.

Topical minoxidil stops hair loss and can stimulate new hair growth in women with androgenic alopecia. 5% topical minoxidil has proven more effective than 2% minoxidil in treating patient with female pattern alopecia. Improvement should be apparent after six months of continuous use. The effects are temporary and hair loss will return once treatment is discontinued.

Patient Management

Emphasize early and often that PCOS can affect multiple organ systems and requires lifelong, regular follow-up. Many patients do not realize that they are risk for developing diabetes, hypertension, and hyperlipidemia. Confirm at each visit that the patient is adhering a regimen of increased exercise and physical activity. Having supportive family members, friends, or a support group like Weight Watchers is indispensible. If needed, refer the patient to a nutritionist.

If lifestyle modification, OCPs, and spironolactone appear to worsen or leave insulin resistance unchanged, look to add an insulin sensitizer such as metformin or even pioglitazone (for lean PCOS women).

Unusual Clinical Scenarios to Consider in Patient Management

When evaluating the patient for PCOS, always keep in mind the multiple and varied clinical presentations. Some women will report having regular menses but these cycles will be anovulatory. Hirsutism is significantly less common in adolescent patients and East Asian women with PCOS. It has been reported that only 20% of Japanese women with PCOS are hirsute. An estimated 40% of women with PCOS exhibit no signs or symptoms of hyperandrogenemia whatsoever. Thus, the absence of any or all classical symptoms should not exclude PCOS on the differential diagnosis.

An interesting syndrome that is considered to be a severe subtype of PCOS is the hyperandrogenism, insulin resistance, and acanthosis nigricans (HAIR-AN) syndrome. There are two types: type A is an inherited form with insulin receptor mutations resulting in severe insulin resistance, type B is less severe, acquired and autoimmune in nature with circulating antibodies against the insulin receptor. It can be associated with other endocrine derangements and is found in 5% of women with PCOS. Insulin, testosterone and androstenedione levels are elevated while the others associated with PCOS are normal. A paraneoplastic variant of acanthosis nigricans has been duly noted, most commonly associated with adenocarcinoma of the gastrointestinal tract, lungs, and uterus. If there are any parameters that indicate a potential malignancy, they should be worked up.

What is the Evidence?

(A thorough review of PCOS with significant detail regarding the pathphysiology, diagnosis, diagnostic pitfalls, and management of the disease. There is a particular emphasis on the systemic associations and excellent clinical tips with respect to approaching the PCOS patient.)

(An excellent and in-depth review focusing on the treatment of the above conditions in PCOS. Most of the paper focuses on systemic therapies/ but it also includes brief mention of both topical agents and mechanical hair removal options.)

(62% percent of patients saw some improvement in symptoms with 2.5mg daily. However, they were also on an OCP with drospirenone. While the concomitant use of the OCP muddles the picture as to which entity caused the improvement, it is recommended that female patients taking finasteride be on at least one form of contraceptive, preferably an OCP.)

(This small study found no significant difference in using 2.5mg vs 5mg of finasteride in hirsute women. It was a follow-up to a study the author's performed earlier using only the 5mg dose. There were both women with PCOS and idiopathic hirsutism included in this study. The investigators did not separate out the responses between the two groups, however. The authors do point out the important point that not only is finasteride equally effective at a low-dose, this is also more cost effective for the patient.)

(Small study whose results are basic but clinically relevant. It concludes that spironolactone is effective and that while side effects are common, they rarely require discontinuation of therapy and often subside with continued treatment. Additionally, the investigators found that DHEAS level but not testosterone levels decreased in their subjects. This finding is interesting in light of the fact that some have postulated that an increased DHEAS is the culprit in PCOS-related acne.)

(This study found no difference in results between spironolactone 200mg daily and cyproterone actetate 50mg (with premarin) or 100mg (with OCP) daily. The majority of patients saw no progression or improvement in their symptoms.)

(A very small study whose results suggest that ketoconazole was more effective than OCP, spironolactone, or cyproterone actetate in the treatment of hirsutism in PCOS. There have been no other follow-up studies but this is an interesting alternative to standard antiandrogen therapies.)

(A recent review of the the literature that concludes that while there is an overall lack of literature regarding whether spironolactone can reduce hirsutism and acne, 100mg spironolactone was effective compared with placebo in the treatment of hirsutism. It also suggests that spironolactone may be more efficacious than other drugs, including finasteride, metformin, and cyproterone acetate.)